Repeated non‐invasive limb ischemic preconditioning attenuates myocardial ischemia‐reperfusion injury in diabetic rats by up‐regulating hexokinase II

Abstract

BackgroundIschemic heart disease is the leading cause of mortality in patients with diabetes mellitus. Although remote ischemic preconditioning achieved by non‐invasively occluding the brachial artery (non‐invasive limb ischemic preconditioning, NLIP) lost its cardioprotection in diabetes, our recent study demonstrated that repeated NLIP (rNLIP, applying 3 cycles of 5 minutes occlusion/5 minutes reperfusion in a unilateral hindlimb daily for 3 days) reduced myocardial infarction, but the mechanism is unclear. Hexokinase II (HKII) is a key glycolytic enzyme that regulates cell survival when bonds to out mitochondrial membrane. However, it is unknown whether HKII is involved in the cardioprotection of diabetic myocardial ischemia/reperfusion(I/R) injury conferred by rNLIP and warrants investigation.Methods and ResultsType 1 diabetic rat model was established by intravenous injection of streptozotocin (60 mg/kg). Myocardial I/R was induced by ligating the left anterior descending artery for 30 minutes followed by 2 hours reperfusion. The results showed that HKII was down‐regulated in the myocardium of diabetic rats(p<0.05, vs. non‐diabetic rats), while myocardial I/R injury was aggravated, as evidenced by increases in post‐ischemic myocardial infarct size, lactate dehydrogenase and circulating levels of troponin I (cardiac injury markers, p<0.05 vs. non‐diabetic rats with I/R), concomitantly with enhanced cardiac apoptosis level (reduced Bcl2/Bax ratio, increased cleaved caspase‐3 level and more TUNEL‐staining positive cells) and aggravated inflammatory responses (increased mRNA levels of pro‐inflammatory cytokines IL1β, IL6 and TNFα). rNLIP significantly up‐regulated the expression of HKII in the myocardium of non‐diabetic and diabetic rats (the up‐regulation level is more pronounced in diabetic rats). The rNLIP‐induced HKII expression in diabetic rats was paralleled by reductions in myocardial infarct size, cardiac apoptosis and inflammatory responses.ConclusionrNLIP attenuates diabetic heart I/R injury through inhibiting cell apoptosis and inflammatory response via up‐regulation of HKII in cardiomyocytes and that targeting HKII expression may be a potential clinical therapeutic intervention for the management of ischemic heart disease in diabetes.Support or Funding InformationThe study was supported by Guangdong Natural Science Foundation (2018A030313535, Guangdong, China) and HMRF (05161826) of Hong Kong.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.